Preparation method and application of a canagliflozin alpha isomer

Abstract

The application discloses a preparation method and application of canagliflozin alpha isomer, and the preparation method comprises the following steps: performing a reduction reaction on a compound of formula IV with a reducing agent in an organic solvent in the presence of a Lewis acid to obtain the canagliflozin alpha isomer, wherein the Lewis acid is a mixture of trifluoroacetic acid and trimethylsilyl trifluoromethanesulfonate; and the reducing agent is 1,1,3,3-tetramethyldisiloxane. The preparation method is simple, high-purity canagliflozin related substance reference substance can be quickly obtained, the yield of the product canagliflozin alpha isomer is 37.5%, the purity is as high as 97.61%, and the purity completely meets the standard reference substance purity requirement, and the product can be used as the standard reference substance, and can be applied to quality control and research of canagliflozin bulk drug, so that the quality control level of the canagliflozin is improved, and the clinical drug safety is ensured.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical chemistry, and more particularly to a preparation method and application of a canagliflozin alpha isomer. BACKGROUND

[0002] Canagliflozin, English name: Canagliflozin, chemical name: (1S)-1,5-dehydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol. Canagliflozin is the first SGLT2 inhibitor drug approved by the US FDA jointly developed by Tanabe Mitsubishi Pharmaceutical Company and Johnson & Johnson, which can make glucose in the renal tubule not be reabsorbed into the blood and be excreted with urine, thereby reducing the blood glucose concentration.

[0003] The canagliflozin isomers are divided into beta and alpha configurations, which are chiral isomers of each other, and the chemical names are (1S)-1,5-dehydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol and (1R)-1,5-dehydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol, respectively, and the specific structural formulas are I and II in the following formula. Among the two isomers of canagliflozin, only the beta configuration of canagliflozin has pharmacological activity.

[0004]

[0005] At present, many literatures have reported the synthesis route of canagliflozin, such as patents CN103936727, CN108191841, CN101801371, etc. However, in the existing synthesis route of canagliflozin, a small amount of canagliflozin alpha isomer impurity is produced, and the impurity is not easy to remove in subsequent processing. Due to the presence of canagliflozin alpha isomer, the purity of canagliflozin is reduced, which affects the quality control of canagliflozin and even endangers the safety of clinical medication.

[0006] Impurity research plays a crucial role in establishing detection methods, analyzing impurity content, and determining reasonable impurity limits. Therefore, the research on canagliflozin alpha isomer impurities is of great significance for the preparation of canagliflozin finished products.

[0007] Currently, there are very few literatures about the preparation method of the α isomer impurity of canagliflozin. Wagschal S et al. (α-C-Glycosides via syn opening of 1,2-anhydro sugars with organozinc compounds in toluene / n-dibutyl ether [J]. J Org Chem, 2015, 80(18): 9328-9335.) disclosed a method for preparing the α isomer of canagliflozin, and the specific synthesis route is as follows:

[0008] However, the method has the disadvantages of difficult way to obtain the reaction raw material, harsh reaction conditions, and easy water absorption of ZnBr2, which is not conducive to actual production operation.

[0009] Therefore, in order to effectively control the quality of canagliflozin, it is necessary to develop a preparation method of the α isomer of canagliflozin which is simple to operate and easy to control the conditions, so as to conveniently and efficiently obtain the α isomer impurity reference substance of canagliflozin, and further apply it to the quality control and research of canagliflozin bulk drug. SUMMARY

[0010] The primary object of the present application is to overcome the defects and shortcomings of the prior art, and to provide a preparation method and application of the α isomer of canagliflozin.

[0011] Another object of the present application is to provide an application of the α isomer of canagliflozin.

[0012] The above objects of the present application are achieved by the following technical solutions:

[0013] A preparation method of the α isomer of canagliflozin, comprising the following steps: in the presence of a Lewis acid, a compound of formula IV (2S, 3R, 4S, 5S, 6R)-2-(3-((5-(4-fluorophenyl)-2-thiophene) methyl)-4-methylphenyl)-6-(hydroxymethyl)-2-methoxy-2H-3, 4, 5-trihydroxytetrahydropyran) is subjected to a reduction reaction with a reducing agent in an organic solvent to obtain the α isomer of canagliflozin shown in formula I; wherein the Lewis acid is a mixture of trifluoroacetic acid and trimethylsilyl triflate; and the reducing agent is 1, 1, 3, 3-tetramethyldisiloxane.

[0014]

[0015] Preferably, the molar ratio of the trifluoroacetic acid to the trimethylsilyl triflate is 9:1 to 1:9.

[0016] More preferably, the molar ratio of the trifluoroacetic acid to the trimethylsilyl triflate is 1:1.

[0017] Preferably, the mass ratio of the Lewis acid to the reducing agent is 0.6:1-1.2:1.

[0018] Preferably, the compound of formula IV is prepared by the following method: taking 2-(5-iodo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene as a starting material, condensing with 2,3,4,6-tetra-O-acetyl-D-gluconic acid-1,5-lactone in toluene in the presence of isopropyl magnesium chloride lithium chloride to obtain a product, and then reacting the product with methanesulfonic acid in methanol to obtain the compound of formula IV.

[0019]

[0020] Preferably, the organic solvent is dichloromethane and / or acetonitrile.

[0021] Preferably, the reaction temperature of the reduction reaction is -15 to -10℃.

[0022] A canagliflozin alpha isomer prepared by any of the above methods, the application of the canagliflozin alpha isomer as an impurity control in the inspection of canagliflozin related substances is also within the protection scope of the present application.

[0023] Compared with the prior art, the present application has the following beneficial effects:

[0024] The present application provides a preparation method of a canagliflozin alpha isomer. The preparation method promotes the generation of the canagliflozin alpha isomer through the mutual synergy of specific Lewis acids. The preparation method is simple, and can quickly obtain a high-purity canagliflozin related substance control. The yield of the product canagliflozin alpha isomer is 37.5%, and the purity is as high as 97.61%, which fully meets the purity requirements of a standard product, and can be used as a standard product. The canagliflozin alpha isomer can be applied to the quality control and research of canagliflozin bulk drug, thereby improving the quality control level of canagliflozin and ensuring the safety of clinical drug use. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 The H-NMR spectrum of the canagliflozin alpha isomer prepared in Example 2 of the present application. DETAILED DESCRIPTION

[0026] In order to more clearly and completely describe the technical solutions of the present application, the present application is further described in detail through specific examples below. It should be understood that the specific examples described herein are only used to explain the present application, and are not used to limit the present application. Various changes can be made within the scope of the present application.

[0027] Example 1

[0028] The preparation method of the compound of formula IV is as follows:

[0029] Into reaction flask A, 52.7 g of the compound of formula II was added, and nitrogen was replaced for 3 times. 105 mL of toluene was added under nitrogen atmosphere, and the temperature was lowered to -5 to -10 °C. Isopropyl magnesium chloride lithium chloride complex tetrahydrofuran solution 129 mL (1.3 mol / L) was slowly added dropwise under nitrogen atmosphere, and the temperature was controlled at -5 to -10 °C. The reaction was stirred for 2 h to obtain the chloromagnesium lithium reagent of the compound of formula II;

[0030] Into another reaction flask B, 50% toluene solution of the compound of formula III 119 g was added, and nitrogen was replaced for 3 times. 105 mL of tetrahydrofuran was added, and the temperature was lowered to -45 to -40 °C. The prepared chloromagnesium lithium reagent of the compound of formula II was added dropwise under nitrogen atmosphere, and the temperature was controlled at -45 to -40 °C. The reaction was carried out for 2 h. 70 mL of dilute hydrochloric acid (concentrated hydrochloric acid and water were mixed in a volume ratio of 0.6:1) was added dropwise, and the temperature was raised to 20 to 25 °C. The organic phase was washed with 180 mL of saturated sodium chloride solution twice. The temperature was gradually raised to 30 to 70 °C, and the organic phase was concentrated under reduced pressure until no solvent was distilled out. 810 mL of methanol and 33.8 g of methanesulfonic acid were added, and the temperature was raised to 40 °C. The reaction was carried out for 4 h. The temperature was lowered to 0 to 10 °C, and 340 mL of saturated sodium bicarbonate solution was added dropwise. The methanol was removed by concentrating under reduced pressure at 40 to 50 °C. 700 mL of ethyl acetate was added, and the water phase was separated. The obtained organic phase was concentrated to obtain the crude compound of formula IV. The compound of formula IV was purified by column chromatography (eluent ratio: dichloromethane:methanol = 50:1 to 15:1) to obtain 22.8 g of the compound of formula IV with a HPLC purity of 99%.

[0031] Example 2

[0032] The preparation method of the α isomer of canagliflozin is as follows:

[0033] Into a reaction flask, 300 mg of the compound of formula IV, 3 mL of dichloromethane and 3 mL of acetonitrile were added, and the temperature was lowered to -20 to -10 °C. A mixture of 72 mg of trifluoroacetic acid and 140 mg of trimethylsilyl trifluoromethanesulfonate (molar ratio 1:1) was added to the system, and nitrogen was replaced for 3 times. 228 mg of 1,1,3,3-tetramethyldisiloxane was added, and the reaction was carried out at -15 to -10 °C for 5 h. 2 mL of saturated sodium bicarbonate solution was added, and the system was distilled under reduced pressure to remove the organic solvent at 40 °C. 10 mL of ethyl acetate and 5 mL of water were added, and the organic phase was separated. The organic phase was dried to obtain 260 mg of the crude compound of formula I, the α isomer of canagliflozin (HPLC purity of the crude compound of formula I: 52%). The crude compound was purified by preparative chromatography to obtain the compound of formula I, the α isomer of canagliflozin (HPLC purity: 97.61%, yield: 37.5%).

[0034] The prepared compound of formula I, the α isomer of canagliflozin, was detected and analyzed:

[0035] ESI-MS (m / z): 490.20 [M+HCOOH] + .

[0036] 1 H NMR (400 MHz, DMSO-d6) δ: 2.25 (s, 3H), 3.42 ~ 3.48 (m, 1H), 3.63 ~ 3.68 (m, 1H), 3.74 ~ 3.79 (m, 1H), 3.81 ~ 3.91 (m, 1H), 3.95 ~ 4.03 (m, 2H), 4.11 (s, 1H), 4.14 ~ 4.15 (m, 1H), 4.41 ~ 4.48 (m, 1H), 4.56 (d, J = 5.5 Hz, 1H), 4.77 (d, J = 4.4 Hz, 1H), 5.02 (d, J = 2.7 Hz, 1H), 5.13 (d, J = 3.9 Hz, 1H), 6.79 (d, J = 3.5 Hz, 1H), 7.10 ~ 7.13 (m, 2H), 7.18 ~ 7.22 (m, 3H), 7.27 (d, J = 3.1 Hz, 1H), 7.59 (dd, J = 8.4, 5.4 Hz, 2H).

[0037] Example 3

[0038] The preparation method of the canagliflozin α isomer is as follows:

[0039] A reaction bottle was charged with 300 mg of the compound of formula IV, 3 mL of dichloromethane and 3 mL of acetonitrile, and cooled to -20 ~ -10 °C. A mixture of 129 mg of trifluoroacetic acid and 28 mg of trimethylsilyl trifluoromethanesulfonate (molar ratio 9:1) was added to the system, replaced with nitrogen for 3 times, and then 228 mg of 1,1,3,3-tetramethyldisiloxane was added. After reaction at -15 ~ -10 °C for 5 h, 2 mL of saturated sodium bicarbonate solution was added, and the organic solvent was removed by distillation under reduced pressure at 40 °C. Then 10 mL of ethyl acetate and 5 mL of water were added, and the organic phase was separated and dried to obtain 250 mg of the crude product of the compound of formula I, canagliflozin α isomer (HPLC purity of the crude product of the compound of formula I: 45%). The crude product was purified by preparative chromatography to obtain the compound of formula I, canagliflozin α isomer (HPLC purity: 95.78%, yield: 30.2%).

[0040] Example 4

[0041] The preparation method of the canagliflozin α isomer is as follows:

[0042] A reaction flask was charged with 300 mg of the compound of formula IV, 3 mL of dichloromethane and 3 mL of acetonitrile, and cooled to -20 to -10 °C. A mixture of 14 mg of trifluoroacetic acid and 252 mg of trimethylsilyl triflate (molar ratio 1:9) was added to the system, and the system was replaced with nitrogen for 3 times. Then 228 mg of 1,1,3,3-tetramethyldisiloxane was added, and the reaction was carried out at -15 to -10 °C for 5 h. Then 2 mL of saturated sodium bicarbonate solution was added, and the organic solvent was removed from the system by distillation under reduced pressure at 40 °C. Then 10 mL of ethyl acetate and 5 mL of water were added, and the organic phase was separated. The organic phase was dried to obtain 250 mg of the crude compound of formula I, canagliflozin α isomer (HPLC purity of the crude compound of formula I: 23%).

[0043] Comparative Example 1

[0044] The preparation method of the canagliflozin α isomer is as follows:

[0045] A reaction flask was charged with 300 mg of the compound of formula IV, 3 mL of dichloromethane and 3 mL of acetonitrile, and cooled to -20 to -10 °C. A mixture of 14 mg of trifluoroacetic acid and 252 mg of trimethylsilyl triflate (molar ratio 1:9) was added to the system, and the system was replaced with nitrogen for 3 times. Then 228 mg of 1,1,3,3-tetramethyldisiloxane was added, and the reaction was carried out at -15 to -10 °C for 5 h. Then 2 mL of saturated sodium bicarbonate solution was added, and the organic solvent was removed from the system by distillation under reduced pressure at 40 °C. Then 10 mL of ethyl acetate and 5 mL of water were added, and the organic phase was separated. The organic phase was dried to obtain 250 mg of the crude compound of formula I, canagliflozin α isomer (HPLC purity of the crude compound of formula I: 23%).

[0046] Comparative Example 2

[0047] The preparation method of the canagliflozin α isomer is as follows:

[0048] A reaction flask was charged with 300 mg of the compound of formula IV, 3 mL of dichloromethane and 3 mL of acetonitrile, and cooled to -20 to -10 °C. A mixture of 14 mg of trifluoroacetic acid and 252 mg of trimethylsilyl triflate (molar ratio 1:9) was added to the system, and the system was replaced with nitrogen for 3 times. Then 228 mg of 1,1,3,3-tetramethyldisiloxane was added, and the reaction was carried out at -15 to -10 °C for 5 h. Then 2 mL of saturated sodium bicarbonate solution was added, and the organic solvent was removed from the system by distillation under reduced pressure at 40 °C. Then 10 mL of ethyl acetate and 5 mL of water were added, and the organic phase was separated. The organic phase was dried to obtain 250 mg of the crude compound of formula I, canagliflozin α isomer (HPLC purity of the crude compound of formula I: 23%).

[0049] The above examples use specific embodiments and tests to make a detailed description of the present application, but some modifications or improvements can be made on the basis of the present application without deviating from the main idea of the present application, which is obvious to those skilled in the art. Therefore, these modifications or improvements made on the basis of the main idea of the present application are within the scope of the present application.

Claims

1. A process for the preparation of a canagliflozin alpha isomer, characterized by, The preparation method comprises the following steps: performing a reduction reaction on a compound (2S, 3R, 4S, 5S, 6R)-2-(3-((5-(4-fluorophenyl)-2-thiophene) methyl)-4-methylphenyl)-6-(hydroxymethyl)-2-methoxy-2H-3, 4, 5-trihydroxytetrahydropyran of formula IV and a reducing agent in an organic solvent in the presence of a Lewis acid to obtain a canagliflozin alpha isomer shown in formula I. The Lewis acid is a mixture of trifluoroacetic acid and trimethylsilyl trifluoromethanesulfonate; the reducing agent is 1, 1, 3, 3-tetramethyldisiloxane; and the molar ratio of the trifluoroacetic acid to the trimethylsilyl trifluoromethanesulfonate is 9:1-1:

9.

2. The production method according to claim 1, wherein The molar ratio of the trifluoroacetic acid to the trimethylsilyl trifluoromethanesulfonate is 1:

1.

3. The production method according to any one of claims 1 to 2, characterized by, The mass ratio of the Lewis acid to the reducing agent is 0.6:1-1.2:

1.

4. The production method according to any one of claims 1 to 2, characterized by, The compound of formula IV is prepared by the following method: taking a compound 2-(5-iodo-2-methylbenzyl)-5-(4-fluorophenyl) thiophene of formula II as a starting material, performing a condensation reaction on the compound II with a compound 2, 3, 4, 6-tetra-O-acetyl-D-gluconic acid-1, 5-lactone of formula III in toluene in the presence of isopropyl magnesium chloride lithium chloride to obtain a product, and performing a reaction on the product in methanol with methanesulfonic acid to obtain the compound of formula IV.

5. The production method according to any one of claims 1 to 2, characterized by, The organic solvent is dichloromethane and / or acetonitrile.

6. The production method according to any one of claims 1 to 2, characterized by, The reaction temperature of the reduction reaction is-15--10℃. The reaction temperature of the reduction reaction is-15--10℃.

Images